RESUMO
Effective therapeutic targets for triple-negative breast cancer (TNBC), a special type of breast cancer (BC) with rapid metastasis and poor prognosis, are lacking, especially for patients with chemotherapy resistance. Decitabine (DCA) is a Food and Drug Administration-approved DNA methyltransferase inhibitor that has been proven effective for the treatment of tumors. However, its antitumor effect in cancer cells is limited by multidrug resistance. Cancer stem cells (CSCs), which are thought to act as seeds during tumor formation, regulate tumorigenesis, metastasis, and drug resistance through complex signaling. Our previous study found that miR-155 is upregulated in BC, but whether and how miR-155 regulates DCA resistance is unclear. In this study, we demonstrated that miR-155 was upregulated in CD24- CD44+ BC stem cells (BCSCs). In addition, the overexpression of miR-155 increased the number of CD24- CD44+ CSCs, DCA resistance and tumor clone formation in MDA-231 and BT-549 BC cells, and knockdown of miR-155 inhibited DCA resistance and stemness in BCSCs in vitro. Moreover, miR-155 induced stemness and DCA resistance by inhibiting the direct target gene tetraspanin-5 (TSPAN5). We further confirmed that overexpression of TSPAN5 abrogated the effect of miR-155 in promoting stemness and DCA resistance in BC cells. Our data show that miR-155 increases stemness and DCA resistance in BC cells by targeting TSPAN5. These data provide a therapeutic strategy and mechanistic basis for future possible clinical applications targeting the miR-155/TSPAN5 signaling axis in the treatment of TNBC.
Assuntos
Decitabina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Tetraspaninas/genética , Neoplasias de Mama Triplo Negativas/genética , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tetraspaninas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
This study was purposed to investigate the serum levels of soluble intracellular adhesion molecule (sVCAM-1), interleukin 18 (IL-18) and vascular endothelial growth factor (VEGF) in patients with aplastic anemia (AA) and their clinical significance. Enzyme linked immunosorbent assay (ELISA) was used to detect sVCAM-1, IL-18 and VEGF in serums of 30 patients with AA and 25 normal controls. The results showed that the serum levels of sVCAM-1 and IL-18 in patients with AA [(839.08 +/- 173.97) ng/ml, (380.35 +/- 47.76) pg/ml] were significantly higher than those in normal controls [(538.16 +/- 91.21) ng/ml, (256.39 +/- 59.52) pg/ml] (p < 0.01; p < 0.01). The levels of sVCAM-1 and IL-18 in severe AA patients [(969.94 +/- 182.54) ng/ml, (388.96 +/- 46.06) pg/ml] were higher than those in chronic AA patients [(709.26 +/- 165.32) ng/ml, IL-18 (352.21 +/- 47.08) pg/ml] (p < 0.01; p < 0.05), but the level of VEGF in AA patients [(69.63 +/- 27.42) pg/ml] was lower than that in the normal controls [(125.62 +/- 32.15) pg/ml] (p < 0.01)]. The level of VEGF in severe AA patients [(51.30 +/- 29.86) pg/ml] was significantly lower than that in chronic AA patients [(80.02 +/- 25.14) pg/ml] (p < 0.01). The levels of sVCAM-1 and IL-18 in AA patients after treatment were lower than those before treatment (p < 0.01; p < 0.05), but the level of VEGF after treatment was significantly higher than that before treatment (p < 0.05). It is concluded that the high levels of sVCAM-1, IL-18 and low level of VEGF in serum may be involved in the pathogenesis and progress of AA.